Composition 064

ABSTRACT

A pharmaceutical composition which comprises N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulphonamide with mannitol and/or microcrystalline cellulose is described.

RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. 119(e) of U.S.Provisional Application No. 60/979,736, filed Oct. 12, 2007 and U.S.Provisional Application No. 61/089,118, filed Aug. 15, 2008. The entireteaching of U.S. 60/979,736 and U.S. 61/089,118 are incorporated hereinby reference.

FIELD OF THE INVENTION

The present application refers to a novel pharmaceutical composition ofN-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulphonamide(hereafter “Compound (I)). More specifically the invention relates to apharmaceutical composition comprising Compound (I) with mannitol and/ormicrocrystalline cellulose, and to methods of treating cancer in a warmblooded animal such as man using this composition.

BACKGROUND OF THE INVENTION

Compound (I) is an endothelin antagonist. The endothelins are a familyof endogenous 21 amino acid peptides comprising three isoforms,endothelin-1 (ET-1), endothelin-2 and endothelin-3. The endothelins areformed by cleavage of the Trp²¹-Val²² bond of their correspondingproendothelins by an endothelin converting enzyme. The endothelins areamong the most potent vasoconstrictors known and have a characteristiclong duration of action. They exhibit a wide range of other activitiesincluding cell proliferation and mitogenesis, extravasation andchemotaxis, and also interact with a number of other vasoactive agents.

The endothelins are released from a range of tissue and cell sourcesincluding vascular endothelium, vascular smooth muscle, kidney, liver,uterus, airways, intestine and leukocytes. Release can be stimulated byhypoxia, shear stress, physical injury and a wide range of hormones andcytokines Elevated endothelin levels have been found in a number ofdisease states in man including cancers.

Recently, endothelin A receptor antagonists have been identified aspotentially of value in the treatment of cancer (Cancer Research, 56,663-668, Feb. 15, 1996 and Nature Medicine, Volume 1, Number 9,September 1999, 944-949).

Cancer affects an estimated 10 million people worldwide. This figureincludes incidence, prevalence and mortality. More than 4.4 millioncancer cases are reported from Asia, including 2.5 million cases fromEastern Asia, which has the highest rate of incidence in the world. Bycomparison, Europe has 2.8 million cases, North America 1.4 millioncases, and Africa 627,000 cases.

In the UK and US, for example, more than one in three people willdevelop cancer at some point in their life. Cancer mortality in the U.S.is estimated to account for about 600,000 a year, about one in everyfour deaths, second only to heart disease in percent of all deaths, andsecond to accidents as a cause of death of children 1-14 years of age.The estimated cancer incidence in the U.S. is now about 1,380,000 newcases annually, exclusive of about 900,000 cases of non-melanotic (basaland squamous cell) skin cancer.

Cancer is also a major cause of morbidity in the UK with nearly 260,000new cases (excluding non-melanoma skin cancer) registered in 1997.Cancer is a disease that affects mainly older people, with 65% of casesoccurring in those over 65. Since the average life expectancy in the UKhas almost doubled since the mid nineteenth century, the population atrisk of cancer has grown. Death rates from other causes of death, suchas heart disease, have fallen in recent years while deaths from cancerhave remained relatively stable. The result is that 1 in 3 people willbe diagnosed with cancer during their lifetime and 1 in 4 people willdie from cancer. In people under the age of 75, deaths from canceroutnumber deaths from diseases of the circulatory system, includingischaemic heart disease and stroke. In 2000, there were 151,200 deathsfrom cancer. Over one fifth (22 percent) of these were from lung cancer,and a quarter (26 percent) from cancers of the large bowel, breast andprostate.

Worldwide, the incidence and mortality rates of certain types of cancer(of stomach, breast, prostate, skin, and so on) have wide geographicaldifferences which are attributed to racial, cultural, and especiallyenvironmental influences. There are over 200 different types of cancerbut the four major types, lung, breast, prostate and colorectal, accountfor over half of all cases diagnosed in the UK and US. Prostate canceris the fourth most common malignancy among men worldwide, with anestimated 400,000 new cases diagnosed annually, accounting for 3.9percent of all new cancer cases.

Current options for treating cancers include surgical resection,external beam radiation therapy and/or systemic chemotherapy. These arepartially successful in some forms of cancer, but are not successful inothers. There is a clear need for new therapeutic treatments.

Compound (I) is exemplified and described in WO96/40681 as Example 36.WO96/40681 claims the endothelin receptors described therein for thetreatment of cardiovascular diseases. The use of Compound (I) in thetreatment of cancers and pain is described in WO04/018044.

Compound (I) has the following structure:

and is also known as zibotentan.

In WO04/018044 an endothelin human receptor binding assay is described.The pIC₅₀ (negative log of the concentration of compound required todisplace 50% of the ligand) for Compound (I) at the ET_(A) receptor was8.27 [8.23-8.32] (n=4). Compound (I) is thus an excellent endothelinantagonist.

WO96/40681 discloses in general terms, certain pharmaceuticallycompositions that may be used to formulate compounds of the inventiondescribed therein (for example see Example 71).

WO04/018044 describes a lactose formulation of Compound (I):

-   -   Compound (I);    -   Lactose monohydrate (filler);    -   Croscarmellose sodium (disintegrant);    -   Povidone (binder);    -   Magnesium stearate (lubricant);    -   Hypromellose (film coat component);    -   Polyethylene glycol 300 (film coat component); and    -   Titanium dioxide (film coat component).

This tablet formulation, based on a lactose monohydrate filler and witha white film coat, was developed for use in Phase I and II clinicalstudies, but proved unsuitable for use in late-stage developmentbecause:

-   -   the tablets were prone to capping and edge-damage;    -   the active ingredient was subject to hydrolytic degradation;    -   the active ingredient was subject to degradation on exposure to        light; and    -   strict controls must be applied to lactose monohydrate to        minimize the risk of TSE (Transmissible Spongiform        Encephalopathy) transmission, as described in EMEA/410/01 Rev. 2        Note for Guidance on Minimising the Risk of Transmitting Animal        Spongiform Encephalopathy Agents via Human and Veterinary        Medicinal Products, (Adopted by CPMP/CVMP October 2003).

The term ‘capping’ means the complete or partial separation of asaucer-shaped disc from the top or bottom surface of a tablet duringcompression of the material to form a tablet or during subsequentprocesses and/or handling. Capping is described in Carstensen, J. T.,Solid pharmaceutics: mechanical properties and rate phenomena, Academicpress, New York (1980) and in Sheth et al., Pharmaceutical dosage forms:Tablets. Vol 1. Ed Liebermann and Lachmann, Pub. Marcel Dekker, New York(1980).

The term ‘edge damage’ means loss of material from the regions where thetablet surfaces intersect, during compression of the material to form atablet or during subsequent processes and/or handling.

Compound (I) is subject to hydrolytic degradation at low and high pH,the principal degradation product being Compound (I) formyl hydrazide:

Over time, Compound (I) formyl hydrazide may further degrade to formCompound (I) hydrazide:

Compound (I) formyl hydrazide and Compound (I) hydrazide are also formedunder hydrolytic conditions upon exposure to light. In the solid state,the principal degradation product following exposure to light isCompound (I) des pyrazine:

In one aspect there is provided Compound (I) formyl hydrazide.

In one aspect there is provided Compound (I) hydrazide.

In one aspect there is provided Compound (I) des pyrazine.

In addition to the above, tablets need to possess sufficient hardness orsufficient mechanical strength, which will prevent a compact frombecoming damaged during subsequent processing or transport. This isrelated to the size of the tablet and when measured in kiloponds (kp) istypically <15 kp. Suitably an immediate release tablet has a hardness inthe range of from 5 to 20 kp, for example about 10 kp.

Friability is the phenomenon whereby tablet surfaces are damaged and/orshow evidence of cracking or breakage when subjected to mechanicalagitation (e.g. during processing, handling or transportation).

Disintegration is the process whereby a tablet breaks down into itsconstituent particles when in contact with a fluid. Disintegration is adesirable property for an immediate release tablet as this leads to anincrease in surface area and hence may lead to an increased rate ofdissolution. In vivo, disintegration should occur as soon as possiblefollowing administration to the gastrointestinal tract, for examplewithin 15 minutes. For immediate release tablets a suitabledisintegration time under the standard United States Pharmacopoeia (USP)disintegration method is in the range of for example about 3 to 15minutes and typically 5 to 8 minutes. Generally in the in-vivo settingimmediate release tablets are not designed to exhibit significantdisintegration in the oral cavity. Rather the disintegration occurs inthe upper GI tract, predominantly in the stomach. An immediate releasetablet formulation may include a disintegrant in order to promote tabletdisintegration.

Immediate release allows the drug to dissolve in the gastrointestinalcontents, with no intention of delaying or prolonging the dissolution orabsorption of the drug (ICH Guideline Q6A: “Specifications: TestProcedures and Acceptance Criteria for New Drug Substances and New DrugProducts: Chemical Substances” Published in the Federal Register, Dec.29, 2000, Volume 65, Number 251, Notices, Page 83041-83063).

Dissolution is the process whereby the active substance is released froma tablet following exposure to a fluid, such that the drug becomesdissolved in the fluid. For testing purposes the fluid is usually chosento simulate conditions within the gastrointestinal tract, and is mostusually an aqueous medium at low or neutral pH. For an immediate releasetablet dissolution should be rapid, for example should be substantiallycomplete within a period of 45 minutes following exposure to fluid understandard test conditions. For example, dissolution measured according tothe general procedure of the USP using Apparatus 2 with 900 mL of 0.1MPhosphate buffer at pH 7.8 as dissolution medium and a stirrer speed of50 rpm. Typical USP acceptance criteria for dissolution from animmediate release tablet for the amount of active ingredient dissolvedis typically 75 to 80% by weight of the active ingredient in the tablet.Tablet hardness, disintegration time and dissolution rate may beinter-related in that an increase in hardness may lead to an increase indisintegration time and hence a decrease in dissolution rate. The targetprofile for an immediate release tablet is one with sufficient hardnessto prevent friability problems, but which disintegrates and dissolvesrapidly within the gastrointestinal tract. An assessment of suitabilitymay commence with the determination of tablet hardness followed, whenappropriate, by more complex tests including disintegration testingand/or dissolution testing.

In an attempt to resolve the issues with the lactose formulationcontaining Compound (I) described above, alternative fillers for acomposition comprising a Compound (I) were investigated. Acceptableresults gave maximum total impurities<1.5% and minimum dissolution of80% for dissolution (as described in the Experimental Section hereinbelow) over 45 minutes.

Tablet cores prepared comprising Compound (I) with calcium phosphatedihydrate (as defined in the European Pharmacopia (PhEur)) (Calipharm™D) as the filler were particularly poor with regard to dissolutionperformance. Similarly the use of magnesium carbonate, heavy (as definedin the PhEur) as the filler led to tablet cores which performed poorlywith regard to impurity levels.

Microcrystalline cellulose is hygroscopic (see for example: ‘Equilibriummoisture content of pharmaceutical excipients’ Callahan, J. C., Cleary,G. W., Elefant, M., et al, Drug Dev Ind Pharm 1982; 8: 355-369) andmoisture pick-up on storage of tablets using that as the filler (leadingto hydrolytic degradation of Compound (I)) was expected. However,surprisingly, we have found that certain tablet compositions containingmicrocrystalline cellulose as one of the excipients do not result in anyundue hydrolytic degradation of Compound (I). Tablet cores comprisingCompound (I) with microcrystalline cellulose as the filler together withcertain other excipients did not exhibit significant capping or edgedamage, gave acceptable results with regard to dissolution performance,and did not exhibit significant chemical degradation when protected fromlight. Some degradation was observed following exposure to light, butthe tablets in this study were not film coated.

Tablet cores prepared comprising Compound (I) with mannitol as thefiller gave acceptable results in hardness experiments even thoughearlier prepared placebo tablet cores (no Compound (I)) with amannitol-based formulation had showed that these tablet cores weresubject to hardening on storage leading to increased disintegrationtimes. These mannitol-based tablet cores were also acceptable withregard to dissolution performance; and although when stored at hightemperature and humidity a deterioration in dissolution performance wasobserved for one of the formulations, this effect was thought to beattributable to the disintegrant and/or binder present in theformulation and was not considered significant with respect to thecriteria used to assess dissolution performance.

Tablet cores with and without Compound (I) with both mannitol andmicrocrystalline cellulose as the fillers were acceptable with regard toboth hardness over time and physical stability. Tablet cores containingCompound (I) with both mannitol and microcrystalline cellulose as thefillers also did not exhibit undue hydrolytic degradation despite thehygroscopic nature of microcrystalline cellulose, and were acceptablewith regard to dissolution.

The formulations of Compound (I) comprising mannitol and/ormicrocrystalline cellulose have one or more advantageous propertiesselected from:

-   -   the formulation uses excipients which are not subject to strict        controls to minimise the possibility of TSE transmission;    -   when the formulation is in the form of a tablet the formulation        is physically stable in that it exhibits one or more of the        following properties:        -   it is not subject to significant capping/edge damage;        -   it shows a reduced tendency to harden on storage;        -   it does not absorb significant quantities of water on            storage; and    -   the formulation is chemically stable in that the levels of        hydrolytic degradation of Compound (I) are low.

SUMMARY OF THE INVENTION

Therefore in one aspect of the present invention there is provided apharmaceutical composition which comprises Compound (I) with mannitoland/or microcrystalline cellulose.

According to a further aspect of the invention there is provided amethod of treating cancer which comprises administering an effectiveamount of a pharmaceutical composition, which comprises Compound (I)with mannitol and/or microcrystalline cellulose, to a warm bloodedanimal such as man.

DETAILED DESCRIPTION OF THE INVENTION

Herein where “mannitol and/or microcrystalline cellulose” is referredto, in one aspect of the invention this refers to mannitol with nomicrocrystalline cellulose. In a further aspect of this invention thisrefers to microcrystalline cellulose and no mannitol. In a furtheraspect of this invention this refers to both mannitol andmicrocrystalline cellulose.

In another aspect of the invention there is provided a pharmaceuticalcomposition which comprises Compound (I), mannitol and microcrystallinecellulose, wherein the weight ratio of mannitol:microcrystallinecellulose is from about 10:1 to about 1:2. For example, the weight ratioof mannitol to microcrystalline cellulose is from about 10:1 to about1:1. In another embodiment the weight ratio of mannitol tomicrocrystalline cellulose is about 8:1 to about 2:1. In a furtherembodiment the weight ratio of mannitol to microcrystalline cellulose isfrom about 7:1 to about 5:1. For example the weight ratio of mannitol tomicrocrystalline cellulose is about 6:1.

Microcrystalline cellulose refers to “Cellulose, microcrystalline” asdescribed in the European Pharmacopoeia (PhEur). The compositionaccording to the invention may use any microcrystalline cellulosesuitable for use in pharmaceutical compositions such as tablets. In oneembodiment the grade of microcrystalline cellulose may be defined byspecific surface area e.g.—1.21-1.30 m²/g for the placebo tablets and1.06-1.12 m²/g for tablets containing Compound (I). In anotherembodiment the microcrystalline cellulose has average particle size inthe range of from about 40 to about 120 μm, for example about 50 toabout 100 μm. In a particular embodiment the microcrystalline cellulosehas an average particle size of about 50 μm. In another particularembodiment the microcrystalline cellulose has an average particle sizeof about 100 μm. Suitably the bulk density of the microcrystallinecellulose is (prior to incorporation into the composition) of about 0.25to about 0.38 g/cm³. For example in one embodiment the bulk density isabout 0.26 to about 0.31 g/cm³. In another embodiment the bulk densityis 0.28 to about 0.33 g/cm³. In one embodiment the microcrystallinecellulose is substantially free from moisture prior to incorporationinto the composition according to the invention (for example containingless than 3, 2 or 1% by weight water). In another embodiment themicrocrystalline cellulose contains about 3 to 6% by weight of waterprior to incorporation into the composition, for example about 5%.Microcrystalline cellulose as used herein may also refer tomicrocrystalline cellulose sold under the trade name Avicel® (ex FMCcorp.). In one embodiment the microcrystalline cellulose is Avicel®PH-101. In another embodiment the microcrystalline cellulose is Avicel®PH-102.

Alternative disintegrants were also investigated. The use ofcroscarmellose sodium (described in the PhEur) as disintegrant was foundto yield lower levels of impurities in comparison with crospovidone.

In one aspect the pharmaceutical composition additionally contains oneor more disintegrants. In another aspect, the pharmaceutical compositionadditionally contains one disintegrant. In another aspect, thepharmaceutical composition additionally contains croscarmellose sodium.Any grade of croscarmellose sodium suitable for pharmaceuticalformulation may be used, for example Ac-Di-Sol (FMC Corp.)

In one aspect the pharmaceutical composition additionally contains oneor more binders. Suitable binders include, for example, lactose,starches, modified starches, sugars, gum acacia, gum tragacanth, guargum, pectin, wax binders, methylcellulose, carboxymethylcellulose,hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, copolyvidone, gelatine, polyvinylpyrollidone (PVP orPovidone) and sodium alginate. In another aspect, the pharmaceuticalcomposition additionally contains one binder selected from lactose,starches, modified starches, sugars, gum acacia, gum tragacanth, guargum, pectin, wax binders, methylcellulose, carboxymethylcellulose,hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, copolyvidone, gelatine, polyvinylpyrollidone (Povidone) andsodium alginate. In another aspect, the pharmaceutical compositionadditionally contains Povidone.

The skilled reader will understand that a component of the tablet canact in more than one capacity. For example in some embodimentsmicrocrystalline cellulose could act as a binder and/or a disintegrantas well as a filler.

Particularly where “Povidone” is referred to this refers to a syntheticwater-soluble homopolymer consisting of N-vinyl pyrrolidone (also knownas 1-vinyl-2-pyrrolidinone polymers; polyvinlypyrrolidone; polyvidone;or PVP). Various grades of povidone are available of varying molecularweights. The grade of the povidone is often denoted by a K value, whichis calculated from dilute solution viscosity measurements, and is usedto denote degree of polymerization or molecular size). A low K valueindicates a low molecular weight and a high K-value a high molecularweight. For example, grade K-12 povidone has an approximate weightaverage molecular weight of 4000, K-17 about 10,000, K-26 about 34,000,K30 about 49,000 and K-29/32 about 58,000. In one embodiment of theinvention the povidone is grade K30. In another embodiment the povidoneis Povidone K29/32 (for example Plasdone™ K29/32). In another embodimentthe povidone is Kollidon™ K30.

In one aspect the pharmaceutical composition additionally contains oneor more lubricants. Suitable lubricants include, for example, magnesiumstearate, stearic acid, palmitic acid, calcium stearate, talc, carnubawax, hydrogenated vegetable oils, mineral oil, polyethylene glycols andsodium stearyl fumarate. In another aspect, the pharmaceuticalcomposition additionally contains one lubricant selected from magnesiumstearate, stearic acid, palmitic acid, calcium stearate, talc, carnubawax, hydrogenated vegetable oils, mineral oil, polyethylene glycols andsodium stearyl fumarate. In another aspect, the pharmaceuticalcomposition additionally contains magnesium stearate.

In one aspect, the pharmaceutical composition contains from 2 to 40% byweight of Compound (I). For example it contains from 2 to 25% by weightof Compound (I). In one embodiment the composition contains 2 to 20% byweight of Compound (I). In particular it contains 4.5 to 8.5% by weightof Compound (I). Suitably the composition according to the invention,such as a capsule or tablet, contains 10 mg of Compound (I). In anotheraspect the composition, such as a capsule or tablet, contains 15 mg ofCompound (I).

In another aspect, the pharmaceutical composition contains from 50 to95% by weight of filler. In another aspect the composition contains from82 to 85% by weight of filler. In particular, it contains 84 to 88% byweight of filler.

In one aspect, the filler is mannitol. In another aspect, the filler ismicrocrystalline cellulose. In another aspect, the filler is mannitoland microcrystalline cellulose. In one embodiment the compositioncontains about 65 to 75% by weight of mannitol, for example about 71 to74% by weight. In another embodiment the composition contains about 10to 15% by weight of microcrystalline cellulose, for example about 12 to13% by weight. In particular, the composition contains 12.5 to 16.5% byweight of microcrystalline cellulose. In another embodiment thecomposition contains from about 65 to 75% by weight of mannitol andabout 10 to 15% by weight of microcrystalline cellulose.

In another aspect, the pharmaceutical composition contains from 1 to 5%by weight of disintegrant. In particular, it contains 2.5 to 3.5% byweight of disintegrant.

In another aspect, the pharmaceutical composition contains from 1 to 5%by weight of binder. In particular, it contains 2.5 to 3.5% by weight ofbinder.

Typically one or more lubricants will be present in an amount from 0.5to 2.5% by weight, particularly 0.75 to 2% by weight and especially 0.75to 1.25% by weight.

In one aspect the invention relates to a pharmaceutical compositioncomprising:

-   -   Compound (I) in an amount of 4.5 to 8.5% by weight;    -   mannitol in an amount of 71 to 76% by weight (for example 71.5        to 75.5% by weight); and    -   microcrystalline cellulose in an amount of 10.5 to 14.5% by        weight.

In another aspect the invention relates to a pharmaceutical compositioncomprising:

-   -   Compound (I) in an amount of 4.5 to 8.5% by weight;    -   mannitol in an amount of 71 to 76% by weight (for example 71.5        to 75.5% by weight);    -   microcrystalline cellulose in an amount of 10.5 to 14.5% by        weight;    -   Croscarmellose sodium in an amount of 2.5 to 3.5% by weight;    -   one or more binders in an amount of 2.5 to 3.5% by weight; and    -   one or more lubricants in an amount of 0.75 to 2.0% by weight        (for example 0.75 to 1.25% by weight.

In another aspect the invention relates to a pharmaceutical compositioncomprising:

-   -   Compound (I) in an amount of 4.5 to 8.5% by weight;    -   mannitol in an amount of 71 to 76% by weight (for example 71.5        to 75.5% by weight);    -   microcrystalline cellulose in an amount of 10.5 to 14.5% by        weight;    -   croscarmellose sodium in an amount of 2.5 to 3.5% by weight;    -   one or more binders in an amount of 2.5 to 3.5% by weight; and    -   magnesium stearate in an amount of 0.75 to 2.0% by weight (for        example 0.75 to 1.25% by weight).

In another aspect the invention relates to a pharmaceutical compositioncomprising:

-   -   Compound (I) in an amount of 4.5 to 8.5% by weight;    -   mannitol in an amount of 71 to 76% by weight (for example 71.5        to 75.5% by weight);    -   microcrystalline cellulose in an amount of 10.5 to 14.5% by        weight;    -   croscarmellose sodium in an amount of 2.5 to 3.5% by weight;    -   Povidone™ (for example Kollidon™ K-30 or Plasdone K29/32) in an        amount of 2.5 to 3.5% by weight; and    -   one or more lubricants in an amount of 0.75 to 2.0% by weight        (for example 0.75 to 1.25% by weight.

In another aspect the invention relates to a pharmaceutical compositioncomprising:

-   -   Compound (I) in an amount of 4.5 to 8.5% by weight;    -   mannitol in an amount of 71 to 76% by weight (for example 71.5        to 75.5% by weight);    -   microcrystalline cellulose in an amount of 10.5 to 14.5% by        weight;    -   croscarmellose sodium in an amount of 2.5 to 3.5% by weight;    -   Povidone™ (for example Kollidon™ K-30 or Plasdone K29/32) in an        amount of 2.5 to 3.5% by weight; and    -   magnesium stearate in an amount of 0.75 to 2.0% by weight (for        example 0.75 to 1.25% by weight).

As will be realised, where herein compositions are described in terms of% by weight of components of the composition, the sum of the % by weightof all of the components of the composition is 100%.

In a further aspect the invention relates to a pharmaceuticalcomposition, as described herein, prepared by direct compression or wetgranulation. The tablets described herein may be prepared bygranulation, in particular wet granulation or direct compression.

In direct compression methods, the drug substance, a compressible fillerand other ingredients, if required, are mixed to a homogeneouscomposition then compressed in a tablet press to produce tablets. Allmaterials used in a direct compression process must be carefullyselected with regard to particle size distribution, density, physicalform in order to avoid segregation during mixing and to ensure suitableflow and compression properties.

Such properties may also be conferred by granulation, which is a processby which primary particles (powders) are made to adhere to form larger,multiparticulate entities called granules. Granulation normallycommences after initial dry mixing of the powdered ingredients so that afairly uniform distribution of ingredients through the mix is achieved.Granulation methods can be divided into two types, wet granulationmethods that utilize a liquid to form the granules and dry methods thatdo not.

Wet granulation involves mixing the components to be granulated as a drymix (for example Compound (I), diluent(s), disintegrant(s) andoptionally a binder). The dry mix is then massed using a granulatingfluid to form granules. Sufficient granulating fluid is added to the drymix to form granules during the granulation process, for example 10 to50% by weight, suitably 15 to 25% by weight, of granulating fluid isadded to the dry mix during the granulation. The granulating fluid maycontain a solvent, which can be removed by drying, and is non-toxic.Suitably however, the granulating fluid is water. The granulating fluidcan be used alone or with a binding agent (binder) to ensure particleadhesion in the dry state. Binding agents can be added to the system asa binder solution (as part of the granulating fluid) or as dry materialmixed with the primary powder particles (as part of the dry mix).Suitably the granulating liquid is added to the dry powder mix in amanner to provide a substantially uniform liquid content in the mixture,for example by spraying the liquid onto the powder during thegranulation. Wet granulators are well known and any suitable granulatormay be used to form the wet granules. There are three main types of wetgranulator, shear granulators (such as planetary mixers), high shearmixer granulators (such as Vector, Fielder or Diosna) and fluid bedgranualtors (such as Aeromatic or Glatt).

Following wet granulation the resulting wet mass may be passed through acourse mesh (for example a 9 mm mesh) to remove any large lumps that mayhave formed during the granulation. The granules are dried to a suitablemoisture content, typically less that 2% by weight water, using asuitable drying method such as fluid bed drying. The resulting granulesare then optionally milled to give a more homogenous particle sizedistribution.

In dry granulation methods, primary powder particles are aggregatedunder pressure (or compaction). There are two main processes: a largetablet (also known as a slug) is produced with a heavy duty tablet pressor the powder particles are compressed between two rollers to produce asheet or ‘ribbon’ of material (process known as roller compaction). Inboth cases, the compacted material is milled using a suitable millingtechnique to produce granular material. The granules can then becompressed in a standard tablet press to produce tablets.

Following granulation the granules might be used in a capsulecomposition or compressed to form a tablet. Suitably to form a tablet,the granules may be blended with a lubricant and then compressed intotablets. A suitable coating may then be applied to the tablets asdescribed herein.

In one aspect there is provided a pharmaceutical composition, asdisclosed herein, prepared by direct compression process that issuitable for oral administration.

In another aspect there is provided a pharmaceutical composition, asdisclosed herein, prepared by a wet granulation process that is suitablefor oral administration.

In another aspect there is provided a pharmaceutical composition, asdisclosed herein, prepared by a dry granulation process that is suitablefor oral administration.

In another aspect the invention relates to a pharmaceutical compositionobtainable by a wet granulation process comprising Compound (I) withmannitol and/or microcrystalline cellulose.

In this wet granulation process aspect of the invention, the presentinventors found that when wet granulation grade mannitol was used, soft,friable tablets were produced. However, when direct compression grademannitol was used in the wet granulation process described herein, thisproblem was avoided.

In a further feature of the present invention the present inventors havefound that they are able to manufacture satisfactory batches of thepreferred composition, using a direct compression grade of mannitol, byboth wet granulation and direct compression processes.

“Direct compression grade mannitol”, for example Parteck™ M grades ofmannitol supplied by Merck Chemicals Ltd., can be produced by a spraydrying process causing the mannitol to crystallise in a needle-likemicrostructure while building up a granular macrostructure. Suitably theaverage particle size of the direct compression grade mannitol is about150 to 350 μm, for example 200 to 300 μm. Suitably the directcompression grade mannitol has a bulk density of about 0.45 to 0.50g/ml. Examples of direct compression grade mannitol prepared by spraydrying include Parteck™ M200, Parteck™ M300, Pearlitol™ SD200 orMannogem™ EZ. In one embodiment of the invention the mannitol isParteck™ M200.

“Wet granulation grade mannitol” generally has a more granular particleshape than direct compression grade mannitol. Suitably the wetgranulation grade mannitol has an average particle size in the range ofabout 200 to 300 μm. For example Pearlitol™ 160 C supplied by RoquetteFreres S.A., comprises cubic crystals having a mean diameter of 160microns.

In another aspect the invention relates to a pharmaceutical compositionobtainable by a wet granulation process comprising Compound (I) withmannitol and/or microcrystalline cellulose wherein direct compressiongrade mannitol is used in the wet granulation process.

In another aspect the invention relates to a pharmaceutical compositionprepared by a wet granulation process comprising Compound (I) withmannitol and/or microcrystalline cellulose wherein direct compressiongrade mannitol is used in the wet granulation process.

Where the composition comprising Compound (I) with mannitol and/ormicrocrystalline cellulose is prepared by wet granulation, particularlydirect compression grade mannitol is used.

In another aspect the invention relates to a pharmaceutical compositionobtainable by a wet granulation process comprising Compound (I),mannitol, microcrystalline cellulose, croscarmellose sodium, a binderand a lubricant.

In another aspect the invention relates to a pharmaceutical compositionobtainable by a wet granulation process comprising Compound (I),mannitol, microcrystalline cellulose, croscarmellose sodium, a binderand magnesium stearate.

In another aspect the invention relates to a pharmaceutical compositionobtainable by a wet granulation process comprising Compound (I),mannitol, microcrystalline cellulose, croscarmellose sodium, Povidoneand a lubricant.

In another aspect the invention relates to a pharmaceutical compositionobtainable by a wet granulation process comprising Compound (I),mannitol, microcrystalline cellulose, croscarmellose sodium, Povidoneand magnesium stearate.

In another aspect the invention relates to a pharmaceutical compositionobtainable by a wet granulation process comprising wet granulation ofCompound (I), mannitol, microcrystalline cellulose, croscarmellosesodium and a binder.

In another aspect the invention relates to a pharmaceutical tabletcomposition obtainable by a wet granulation process comprising:

(i) wet granulation of Compound (I), mannitol, microcrystallinecellulose, croscarmellose sodium and a binder;

(ii) blending the resulting granules with a lubricant; and

(iii) compressing the mixture from step (iii) into tablets.

In these embodiments any of the mannitol, microcrystalline cellulose,croscarmellose sodium, binder and lubricants described herein may beused. In a particular embodiment the mannitol is a direct compressiongrade mannitol such as Parteck M200.

In one aspect the pharmaceutical composition is in a solid dosage form,such as a tablet or capsule. In another aspect the pharmaceuticalcomposition is in the form of a tablet. In a further feature of theinvention the composition is in the form of a tablet designed forimmediate release. Suitably the immediate release tablet willdisintegrate quickly following administration as hereinbefore described.For example, typically represented by in-vitro dissolution times ofabout 3 to 15 minutes and typically 5 to 8 minutes.

According to a further aspect of the invention there is provided aprocess for the preparation of a pharmaceutical composition according tothe invention comprising mixing compound (I) and the mannitol and/ormicrocrystalline cellulose and forming the mixture into a unit dosageform such as a tablet or capsule.

In one embodiment of the process, following mixing of compound (I) andthe mannitol and/or microcrystalline cellulose (and other optionalingredients as required such as a binder and disintegrant ashereinbefore described) the mixture is granulated and formed into asuitable unit dosage form. Suitable granulation methods are ashereinbefore described. For example the mixture may be wet granulated asdescribed herein. When a binder is used in the composition the bindersuch as PVP may be incorporated into the mixture prior to granulation asa dry powder. Alternatively, the binder may be added as a solution ordispersion with the wet granulation liquid. Following granulation thegranules may be dried and milled and, for example, compressed into atablet as described hereinbefore. Suitably the composition is providedwith a means for protecting Compound (I) from light degradation asdescribed hereinafter. For example, when the composition is in the formof a tablet, the tablet is provided with a light protective coating asdescribed hereinafter.

Accordingly, a further aspect of the invention there is provides aprocess for the preparation of a pharmaceutical immediate release tabletcomposition according to the invention comprising:

(i) mixing Compound (I) and the mannitol and/or microcrystallinecellulose;

(ii) granulating the mixture formed in step (i) to form granules;

(iii) optionally milling the granules;

(iv) mixing the granules with a lubricant; and

(v) compressing the granules into a tablet.

Additional excipients such as a disintegrant and binder may be includedin the mixture in step (i) of the process as described hereinbefore andillustrated in the examples.

In a particular embodiment the granulation step (ii) is a wetgranulation as described hereinbefore. When the granulation step (ii) isa wet granulation, the granules are suitably dried prior to milling (ifcarried out) and subsequent compression into tablets.

In a further embodiment of the process for the preparation of thepharmaceutical immediate release tablet composition, the process furthercomprises coating the tablets from step (v) with a film coating.

Compound (I) exists in certain crystalline forms. In a particular aspectof the invention, Compound (I) exists in a crystalline form, referred toas Form 1 in the Cambridge crystallographic database.[N-(3-Methoxy-5-methylpyrazin-2-yl)-244-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide(ZD4054 Form 1). Acta Crystallographica, Section E: Structure ReportsOnline (2004), E60(10), o1817-o1819].

In another aspect the invention relates to a pharmaceutical compositionas hereinabove defined in which Compound (I) is in a crystalline form.

In yet another aspect the invention relates to a pharmaceuticalcomposition as hereinbefore defined comprising Compound (I)substantially as Form 1.

Substantially as Form 1 means that there is greater than 95% of Form 1present. In particular there is greater than 96% Form 1. Particularlythere is greater than 97% Form 1. In particular there is greater than98% Form 1. Particularly there is greater than 99% Form 1. In particularthere is greater than 99.5% Form 1. Particularly there is greater than99.8% Form 1.

As mentioned hereinbefore, when the composition is in the form of atablet, the tablet is suitably coated with a film. We have found thattablet cores coated with a non-pigmented (white) film coating at a levelof 2.3% up to about 3.25% relative to the core weight exhibited chemicaldegradation of Compound (I) following exposure to light. Tablet corescoated with a film coat, including iron oxide pigments, at a level of3.5% relative to the core weight, did not exhibit significant chemicaldegradation following exposure to light. Coatings with lower levels offilm coatings containing iron oxide pigments may reduce lightdegradation of Compound (I) compared to the use of a white film coatcontaining titanium dioxide. In one embodiment of the invention thecomposition is in the form of a tablet coated with a coating, suitably afilm coating, comprising a ferric oxide. In this embodiment the ferricoxide is suitably present at about 0.025 to 0.075% by weight of thetablet, for example about 0.05% by weight of the tablet. The ferricoxide coating may be applied using for example a commercially availablecoating such as the Opadry™ films supplied by Colorcon Inc.

The formulation of Compound (I) comprising a pigmented (in particularbeige) film-coat meets the requirements for a pharmaceutical soliddosage form in late-stage pharmaceutical development in that theformulation is chemically stable in that the levels of light-induceddegradation are low.

In one aspect the pharmaceutical composition is a tablet with a coatingcomprising one or more colouring agents. In another aspect, thepharmaceutical composition is a tablet with a coating comprising threecolouring agents. In another aspect, the pharmaceutical composition is atablet with a coating comprising an iron oxide pigment. In anotheraspect, the pharmaceutical composition is a tablet with a coatingcomprising iron oxide pigments. In another aspect, the pharmaceuticalcomposition is a tablet with a coating comprising iron oxide yellow,iron oxide red and iron oxide black. Coatings containing iron oxidepigments are commercially available, for example Opadry Beige (Colorcon03B27164), which may be applied to the tablet as an aqueous solution orsuspension.

In one aspect the pharmaceutical composition is a tablet with a weightof coating between, for example 1 to 10%, such as 2 and 10% by weight ofthe tablet core weight, for example 3 to 6% by weight of the tablet coreweight. In particular, the weight of coating is 3 to 4% by weight of thetablet core weight. In another embodiment the weight of the coating isfrom about 1 to about 2% by weight of the tablet core weight.

In one aspect the pharmaceutical composition is a tablet with a coatingcomprising one or more film formers. In another aspect, thepharmaceutical composition is a tablet with a coating comprising onefilm former. In another aspect, the pharmaceutical composition is atablet with a coating comprising a water-soluble film-former such as ahydroxypropylmethyl cellulose, for example, Hypromellose 2910 (definedin the PhEur).

In one aspect the pharmaceutical composition is a tablet with a coatingcomprising one or more opacifiers. In another aspect, the pharmaceuticalcomposition is a tablet with a coating comprising one opacifier. Inanother aspect, the pharmaceutical composition is a tablet with acoating comprising titanium dioxide.

In one aspect the pharmaceutical composition is a tablet with a coatingcomprising one or more plasticisers. In another aspect, thepharmaceutical composition is a tablet with a coating comprising oneplasticiser. In another aspect, the pharmaceutical composition is atablet with a coating comprising a polyethylene glycol plasticiser, forexample Macrogol 400 (defined in the PhEur).

Tablet coating may be carried out using conventional methods well knownin the art, for example coating in a pan coater. The film coat may beapplied by spraying an aqueous suspension of the film former, opacifier,plasticiser and colouring agents onto the tablet cores.

In another aspect the invention relates to a pharmaceutical compositioncomprising a Compound of formula (I) which is a tablet with a coatingcomprising iron oxide yellow, iron oxide red and iron oxide black.

In another aspect the invention relates to a pharmaceutical compositioncomprising a Compound of formula (I) which is a tablet with a coatingcomprising Hypromellose 2910, titanium dioxide, Macrogol 400, iron oxideyellow, iron oxide red and iron oxide black.

In another aspect the invention relates to a tablet comprising a corecomprising a Compound of formula (I) with mannitol and/ormicrocrystalline cellulose and a coating comprising iron oxide yellow,iron oxide red and iron oxide black.

In another aspect the invention relates to a tablet comprising a corecomprising a Compound of formula (I) with mannitol and/ormicrocrystalline cellulose and a coating comprising Hypromellose 2910,titanium dioxide, Macrogol 400, iron oxide yellow, iron oxide red andiron oxide black.

In another aspect, the coating contains from 50 to 75% by weight of filmformer. In particular, it contains 60.5 to 64.5% by weight of filmformers.

In another aspect, the coating contains from 20 to 40% by weight ofopacifier. In particular, it contains 27.5 to 31.5% by weight ofopacifier.

In another aspect, the coating contains from 5 to 20% by weight ofplasticiser. In particular, it contains 4.5 to 8.5% by weight ofplasticiser.

In another aspect, the coating contains from 0.5 to 10% by weight ofcolouring agent. In particular, it contains 1-2% by weight of colouringagent.

In another aspect, the coating contains from 0.025 to 0.075% by weightof iron oxide pigment(s).

In another aspect, the coating contains from 0.025 to 0.075% by weightof iron oxide pigment(s) and from 0.8 to 1.2% by weight of titaniumdioxide. For example a coating containing about 0.05% iron oxide andabout 1% by weight of titanium dioxide, wherein the weights are % weightrelative to the weight of the tablet core to which the coating isapplied.

-   -   In one aspect the invention relates to a pharmaceutical        composition comprising a tablet core and a coating wherein the        tablet core comprises:    -   Compound (I) in an amount of 4.5 to 8.5% by weight of the core;    -   mannitol in an amount of 71.5 to 75.5% by weight of the core;        and    -   microcrystalline cellulose in an amount of 10.5 to 14.5% by        weight of the core; and wherein the coating on the tablet core        comprises:    -   iron oxide yellow in an amount of 0.75 to 1.75% by weight of the        coating;    -   iron oxide red in an amount of 0.1 to 0.6% by weight of the        coating; and    -   iron oxide black in an amount of 0.06 to 1% by weight of the        coating.

In another aspect the invention relates to a pharmaceutical compositioncomprising a core comprising Compound of formula (I) and a coatingcomprising:

-   -   a water-soluble film-former such as Hypromellose 2910 in an        amount of 60.5 to 64.5% by weight;    -   titanium dioxide in an amount of 27.5 to 31.5% by weight;    -   a polyethylene glycol plasticiser such as Macrogol 400 in an        amount of 4.5 to 8.5% by weight;    -   iron oxide yellow in an amount of 0.75 to 1.75% by weight;    -   iron oxide red in an amount of 0.1 to 0.6% by weight; and    -   iron oxide black in an amount of 0.06 to 1% by weight; wherein        the weights are % by weight of the coating.

In another aspect the invention relates to a pharmaceutical compositioncomprising a core comprising a Compound of formula (I) and mannitol withoptional microcrystalline cellulose and a coating comprising:

-   -   a water-soluble film-former such as Hypromellose 2910 in an        amount of 60.5 to 64.5% by weight;    -   titanium dioxide in an amount of 27.5 to 31.5% by weight;    -   a polyethylene glycol plasticiser such as Macrogol 400 in an        amount of 4.5 to 8.5% by weight;    -   iron oxide yellow in an amount of 0.75 to 1.75% by weight;    -   iron oxide red in an amount of 0.1 to 0.6% by weight; and    -   iron oxide black in an amount of 0.06 to 1% by weight; wherein        the weights are % by weight of the coating.

In another aspect the invention relates to a pharmaceutical immediaterelease tablet composition comprising a tablet core and a coating,wherein the tablet core comprises:

-   -   Compound of formula (I) in an amount of 6.0 to 8.0% by weight of        the tablet core;    -   mannitol in an amount of 72.0 to 75.0% by weight of the tablet        core;    -   microcrystalline cellulose in an amount of 10.5 to 14.5% by        weight of the tablet core;    -   croscarmellose sodium in an amount of 2.5 to 4.5% by weight of        the tablet core; and    -   PVP (for example, Kollidon™ K30 or Plasdone™ K29/32) in an        amount of 2.5 to 4.5% by weight of the tablet core; and    -   a lubricant (for example magnesium stearate) in an amount of        0.75 to 2.0% by weight (for example 0.8 to 1.75% by weight);        and wherein the coating on the tablet core comprises an iron        oxide pigment and wherein the coating is present in an amount of        3 to 6% by weight of the tablet core.

In another aspect the invention relates to a pharmaceutical immediaterelease tablet composition comprising a tablet core and a coating,wherein the tablet core comprises:

-   -   Compound of formula (I) in an amount of 6.0 to 8.0% by weight of        the tablet core;    -   mannitol in an amount of 72.0 to 75.0% by weight of the tablet        core;    -   microcrystalline cellulose in an amount of 10.5 to 14.5% by        weight of the tablet core;    -   croscarmellose sodium in an amount of 2.5 to 4.5% by weight of        the tablet core; and    -   PVP (suitably Collidon-K30 or Plasdone K29/32) in an amount of        2.5 to 4.5% by weight of the tablet core; and    -   a lubricant (for example magnesium stearate) in an amount of        0.75 to 2.0% by weight (for example 0.8 to 1.75% by weight);        and wherein the coating on the tablet core comprises:    -   a water-soluble film-former such as Hypromellose 2910 in an        amount of 60.5 to 64.5% by weight of the coating;    -   titanium dioxide in an amount of 27.5 to 31.5% by weight of the        coating;    -   a polyethylene glycol plasticiser such as Macrogol 400 in an        amount of 4.5 to 8.5% by weight of the coating;    -   iron oxide yellow in an amount of 0.75 to 1.75% by weight of the        coating;    -   iron oxide red in an amount of 0.1 to 0.6% by weight of the        coating; and    -   iron oxide black in an amount of 0.06 to 1% by weight of the        coating.        Suitably in this embodiment the coating is present in an amount        of 2.5 to 5% by weight of the tablet core, for example about        3.5% by weight of the tablet core.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose for use as a medicament.

Therefore according to this aspect of the present invention, there isprovided a pharmaceutical composition which comprises Compound (I) withmannitol and/or microcrystalline cellulose, for the treatment of cancerin a warm blooded animal such as man.

According to another feature of the present invention, there is providedthe use of a pharmaceutical composition which comprises Compound (I)with mannitol and/or microcrystalline cellulose, for the manufacture ofa medicament for the treatment of cancer in a warm blooded animal suchas man.

According to a further feature of this aspect of the invention there isprovided a method of treating cancer which comprises administering aneffective amount of a pharmaceutical composition which comprisesCompound (I) with mannitol and/or microcrystalline cellulose, to a warmblooded animal such as man.

In another aspect of the invention there is provided a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose, for the reduction of abnormal proliferationin a cancerous cell or inducing differentiation of a cancerous cell in awarm blooded animal such as man.

In another aspect of the invention there is provided the use of apharmaceutical composition which comprises Compound (I) with mannitoland/or microcrystalline cellulose, for the manufacture of a medicamentfor the reduction of abnormal proliferation in a cancerous cell orinducing differentiation of a cancerous cell in a warm blooded animalsuch as man.

In another aspect of the invention there is provided a method forreducing abnormal proliferation in a cancerous cell or inducingdifferentiation of a cancerous cell which comprises administering aneffective amount of a pharmaceutical composition which comprisesCompound (I) with mannitol and/or microcrystalline cellulose, to a warmblooded animal such as man.

In another aspect of the invention there is provided a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose, for inducing apoptosis in a cancerous cellin a warm blooded animal such as man.

In another aspect of the invention there is provided the use of apharmaceutical composition which comprises Compound (I) with mannitoland/or microcrystalline cellulose, for the manufacture of a medicamentfor inducing apoptosis in a cancerous cell in a warm blooded animal suchas man.

In another aspect of the invention there is provided a method ofinducing apoptosis in a cancerous cell which comprises administering aneffective amount of a pharmaceutical composition which comprisesCompound (I) with mannitol and/or microcrystalline cellulose, to a warmblooded animal such as man.

In another aspect of the invention there is provided a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose, for an anti-angiogenic and vasculartargeting agent in blood vessels supplying a cancerous cell in a warmblooded animal such as man.

In another aspect of the invention there is provided the use of apharmaceutical composition which comprises Compound (I) with mannitoland/or microcrystalline cellulose, for the manufacture of a medicamentfor an anti-angiogenic and vascular targeting agent in blood vesselssupplying a cancerous cell in a warm blooded animal such as man.

In another aspect of the invention there is provided a method ofproviding an anti-angiogenic and vascular targeting agent in bloodvessels supplying a cancerous cell which comprises administering aneffective amount of a pharmaceutical composition which comprisesCompound (I) with mannitol and/or microcrystalline cellulose, to a warmblooded animal such as man.

By the term “vascular targeting agent” it is to be understood that thesite of action of a pharmaceutical composition which comprises Compound(I) with mannitol and/or microcrystalline cellulose would be on thevasculature itself rather than the tumour.

In another aspect of the invention there is provided a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose, as an anti-angiogenic agent in a warmblooded animal such as man.

In another aspect of the invention there is provided the use of apharmaceutical composition which comprises Compound (I) with mannitoland/or microcrystalline cellulose, for the manufacture of a medicamentfor an anti-angiogenic agent in a warm blooded animal such as man.

In another aspect of the invention there is provided a method ofproviding an anti-angiogenic effect which comprises administering aneffective amount of a pharmaceutical composition which comprisesCompound (I) with mannitol and/or microcrystalline cellulose, to a warmblooded animal such as man.

In another aspect of the invention there is provided a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose, as an inhibitor of bone metastases and aninhibitor of invasion in a warm blooded animal such as man.

In another aspect of the invention there is provided the use of apharmaceutical composition which comprises Compound (I) with mannitoland/or microcrystalline cellulose, for the manufacture of a medicamentfor an inhibitor of bone metastases and an inhibitor of invasion in awarm blooded animal such as man.

In another aspect of the invention there is provided a method ofinhibiting bone metastases and inhibiting invasion which comprisesadministering an effective amount of a pharmaceutical composition whichcomprises Compound (I) with mannitol and/or microcrystalline cellulose,to a warm blooded animal such as man.

In another aspect of the invention there is provided a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose, as an inhibitor of bone metastases in a warmblooded animal such as man.

In another aspect of the invention there is provided the use of apharmaceutical composition which comprises Compound (I) with mannitoland/or microcrystalline cellulose, for the manufacture of a medicamentfor an inhibitor of bone metastases in a warm blooded animal such asman.

In another aspect of the invention there is provided a method ofinhibiting bone metastases which comprises administering an effectiveamount of a pharmaceutical composition which comprises Compound (I) withmannitol and/or microcrystalline cellulose, to a warm blooded animalsuch as man.

In another aspect of the invention there is provided a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose, for the prevention of bone metastases in awarm blooded animal such as man.

In another aspect of the invention there is provided the use of apharmaceutical composition which comprises Compound (I) with mannitoland/or microcrystalline cellulose, for the manufacture of a medicamentfor the prevention of bone metastases in a warm blooded animal such asman.

In another aspect of the invention there is provided a method ofpreventing bone metastases which comprises administering an effectiveamount of a pharmaceutical composition which comprises Compound (I) withmannitol and/or microcrystalline cellulose, to a warm blooded animalsuch as man.

In another aspect of the invention there is provided a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose, for the treatment of bone metastases in awarm blooded animal such as man.

In another aspect of the invention there is provided the use of apharmaceutical composition which comprises Compound (I) with mannitoland/or microcrystalline cellulose, for the manufacture of a medicamentfor the treatment of bone metastases in a warm blooded animal such asman.

In another aspect of the invention there is provided a method oftreating bone metastases which comprises administering an effectiveamount of a pharmaceutical composition which comprises Compound (I) withmannitol and/or microcrystalline cellulose, to a warm blooded animalsuch as man.

In a further aspect of the invention, there is provided the inhibition,treatment and/or prevention of bone metastases, as described herein,wherein the bone metastases are as a result of renal, thyroid, lung,breast or prostate cancer.

In another aspect of the invention there is provided a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose, for the prevention or treatment of painassociated with elevated endothelin-1 production in a warm bloodedanimal such as man.

In another aspect of the invention there is provided the use of apharmaceutical composition which comprises Compound (I) with mannitoland/or microcrystalline cellulose, for the manufacture of a medicamentfor the prevention or treatment of pain associated with elevatedendothelin-1 production in a warm blooded animal such as man.

In another aspect of the invention there is provided a method oftreating pain associated with elevated endothelin-1 production whichcomprises administering an effective amount of a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose, to a warm blooded animal such as man.

In another aspect of the invention there is provided a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose, for the prevention or treatment of pain in awarm blooded animal such as man.

In another aspect of the invention there is provided the use of apharmaceutical composition which comprises Compound (I) with mannitoland/or microcrystalline cellulose, for the manufacture of a medicamentfor the prevention or treatment of pain in a warm blooded animal such asman.

In another aspect of the invention there is provided a method oftreating pain which comprises administering an effective amount of apharmaceutical composition which comprises Compound (I) with mannitoland/or microcrystalline cellulose, to a warm blooded animal such as man.

In another aspect of the invention there is provided a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose, for the prevention or treatment of painassociated with stimulation of the ET_(A) receptor in a warm bloodedanimal such as man.

In another aspect of the invention there is provided the use of apharmaceutical composition which comprises Compound (I) with mannitoland/or microcrystalline cellulose, for the manufacture of a medicamentfor the prevention or treatment of pain associated with stimulation ofthe ET_(A) receptor in a warm blooded animal such as man.

In another aspect of the invention there is provided a method oftreating pain associated with stimulation of the ET_(A) receptor whichcomprises administering an effective amount of a pharmaceuticalcomposition which comprises Compound (I) with mannitol and/ormicrocrystalline cellulose, to a warm blooded animal such as man.

Where cancer is referred to, particularly it refers to oesophagealcancer, myeloma, hepatocellular, pancreatic, cervical cancer, ewingstumour, neuroblastoma, Kaposis sarcoma, ovarian cancer, breast cancer,colorectal cancer, prostate cancer, bladder cancer, melanoma, lungcancer—non small cell lung cancer (NSCLC), and small cell lung cancer(SCLC)-gastric cancer, head and neck cancer, renal cancer, lymphoma andleukaemia. More particularly it refers to prostate cancer. In addition,more particularly it refers to SCLC, NSCLC, colorectal cancer, ovariancancer and/or breast cancer. In addition, more particularly it refers toprostate cancer, NSCLC, ovarian cancer, bladder cancer, gastric cancerand/or breast cancer. In addition, more particularly it refers toprostate cancer, NSCLC, ovarian cancer, bladder cancer and/or gastriccancer. In addition, more particularly it refers to prostate cancer,NSCLC, ovarian cancer and/or bladder cancer. In addition, moreparticularly it refers to SCLC. In addition, more particularly it refersto NSCLC. In addition, more particularly it refers to colorectal cancer.In addition, more particularly it refers to ovarian cancer. In addition,more particularly it refers to breast cancer. Furthermore, moreparticularly it refers to bladder cancer, oesophageal cancer, gastriccancer, melanoma, cervical cancer and/or renal cancer. In addition itrefers to endometrial, liver, stomach, thyroid, rectal and/or braincancer. In another aspect of the invention, the cancer is not melanoma.In another embodiment of the invention, particularly the cancer is in ametastatic state, and more particularly the cancer produces metastasesto the bone. In a further embodiment of the invention, particularly thecancer is in a metastatic state, and more particularly the cancerproduces skin metastases. In a further embodiment of the invention,particularly the cancer is in a metastatic state, and more particularlythe cancer produces lymphatic metastases. In a further embodiment of theinvention, the cancer is in a non-metastatic state.

It is to be understood that when the cancer is in a metastatic state,that a pharmaceutical composition which comprises Compound (I) withmannitol and/or microcrystalline cellulose acts at both the primarytumour site and the metastases by prevention, treatment and inhibitionof metastases.

The composition according to the invention may be used alone for thetreatment of cancer. Alternatively, the composition according to theinvention may also be used in combination with certain other anti-canceragents for the treatment of cancer as described in WO2004/035057,WO2005/023264 and WO2006/056760. For example, the composition accordingto the invention may be useful in combination with docetaxel for thetreatment of hormone resistant prostate cancer, particularly metastatichormone resistant prostate cancer, more particularly metastatic hormoneresistant prostate cancer in patients who are asymptomatic or mildlysymptomatic for pain.

In one aspect of the invention, where pain is referred to, this is painassociated with raised endothelin-1 levels. In another aspect of theinvention this is pain associated with stimulation of the ET_(A)receptor resulting from situations where ET_(B) down-regulation hasoccurred leading to abnormal ET_(A) stimulation and/or elevation ofendothelin-1 levels. Particularly this is pain associated with cancer.More particularly it is pain associated with prostate cancer.

Additionally, a pharmaceutical composition which comprises Compound (I)with mannitol and/or microcrystalline cellulose is expected to be usefulin the treatment and/or prophylaxis of pain of different origins andcauses, including acute as well as chronic pain states. Examples arepain caused by chemical, mechanical, radiation (including sunburn),thermal (including burns), infectious or inflammatory tissue trauma orcancer, postoperative pain, post-partum pain, the pain associated withjoint conditions (such as rheumatoid arthritis and osteoarthritis), painassociated with dental conditions (such as dental caries andgingivitis), myofascial and low back pain, pain associated with bonedisorders (such as osteoporosis, hypercalcaemia of malignancy andPaget's disease) and the pain associated with sports injuries andsprains.

Also neuropathic pain conditions of central or peripheral origin couldbe treated or prevented with a pharmaceutical composition whichcomprises Compound (I) with mannitol and/or microcrystalline cellulose.Examples of these pain conditions are pain associated with trigeminalneuralgia, pain associated with postherpetic neuralgia (PHN), painassociated with diabetic mono/poly neuropathy, pain associated withnerve trauma, pain associated with spinal cord injury, pain associatedwith central post stroke, pain associated with multiple sclerosis andpain associated with Parkinson's disease.

Other pain states of visceral origin such as caused by ulcer,dysmenorrhea, endometriosis, irritable bowel syndrome, dyspepsia etc.could also be treated or prevented with a pharmaceutical compositionwhich comprises Compound (I) with mannitol and/or microcrystallinecellulose.

A further aspect of the invention is to use a pharmaceutical compositionwhich comprises Compound (I) with mannitol and/or microcrystallinecellulose for oral treatment of neuropathic or central pain states.

It is to be understood that the uses and methods of treatment describedherein may use any of the compositions comprising Compound (I) withmannitol and/or microcrystalline cellulose described herein.

General Experimental Materials

Material Pharmacopoeia Function Example Supplier Mannitol PhEur¹,USP-NF², JP³ Filler (direct Parteck ™ M200 Merck Chemicals compression)EMPROVE ® Ltd. (UK) Filler (wet Pearlitol ™ 160 C Roquette Freresgranulation) S.A. (France) Cellulose, Ph Eur, USP-NF, JP Filler Avicel ®PH-101 FMC Biopolymer microcrystalline (Ireland) Magnesium PhEur,USP-NF, JP Filler L.M. Loveridge Ltd. (UK) carbonate, heavy Calciumphosphate USP-NF Filler Calipharm D Innophos (USA) dihydrate PovidonePhEur, USP-NF, JP Binder Plasdone ™ K29/32 ISP Technologies,Croscarmellose PhEur, USP-NF, JP Disintegrant AcDiSol ™ SD-711 FMCBiopolymer sodium (Ireland) Crospovidone PhEur, USP-NF DisintegrantPolyplasdone ® International Specialty Products (USA) Magnesium stearatePhEur, USP-NF, JP Lubricant Magnesium Stearate NF Mallinckrodt Inc.(USA) Non-Bovine HyQual ® Hypromellose PhEur, USP-NF, JP Film formerOpadry ™ Beige⁴ Colorcon Limited (UK) Titanium dioxide PhEur, USPOpacifier Iron oxide, black Pigment (Fe₃O₄, magnetite, CAS#1317-61-9)Iron oxide, red (Fe₂O₃, haematite, CAS#1309-37-1 Iron oxide, yellow(Fe(OH)₃, goethite, CAS#20344-49-4) Polyethylene glycol PhEur(Macrogols), Plasticiser USP-NF, JP (Macrogol) ¹PhEur: EuropeanPharmacopoeia 5^(th) Edition (Directorate for the Quality of Medicinesof the Council of Europe) 2007. ²USP-NF: United States Pharmacopeia30/National Formulary 25 (The United States Pharmacopeia Convention)2007. ³JP: Japanese Pharmacopeia 15^(th) Edition, English Version(Society of Japanese Pharmacopoeia) 2006. ⁴The film-coat may be suppliedas a proprietary concentrate (eg, Opadry, product identifier 03B27164)or powder mixture that requires reconstitution in purified water, priorto application as an aqueous suspension to the tablet cores.

Hardness

Hardness testing was carried out using a Schleuniger Hardness TesterModel 6D or equivalent, in accordance with the procedure specified inthe European Pharmacopoeia (Resistance to crushing of tablets), exceptthat the number of tablets tested was as specified in the table. Thehardness of each tablet was measured along its diameter. The average‘hardness’ is reported in kiloponds (kp).

Disintegration Time

Disintegration time was measured out in accordance with the procedurespecified in the European Pharmacopoeia, without a disc and using wateras the medium. Disintegration time is reported in minutes (min.).

Compound (I) Assay and Impurities

The Compound (I), Compound (I) formyl hydrazide, and total impuritiescontents were determined using High Performance Liquid ChromatographyHPLC. 10 μL sample was injected into a mobile phase comprisingwater/acetonitrile/formic acid in the ratios 900:100:2 (EluentA)/400:600:2 (Eluent B), as defined by the gradient program in Table 1below.

The solution for the impurities determination is prepared by extractionfrom a known weight of finely ground tablets using 1:1acetonitrile:water as extraction solvent, followed by filtration througha 0.45 micron PTFE filter, such that the target concentration ofCompound (I) in the test solution is 0.25 mg/mL.

TABLE 1 Gradient programme - Compound (I) assay and impurities Gradientprogramme Time (mins) % A % B 0 100 0 50 0 100 51 100 0 60 100 0

The mobile phase starts as 100% eluent A at time zero, then thecomposition is modified by increasing the proportion of eluent Bgradually and linearly such that after 50 minutes the mobile phasecomprises 100% eluent B. This composition is maintained for 1 minute,then reverts to 100% eluent A in order to re-equilibrate the column.

Separation of impurities was performed using a column 15 cm long×4.6 mminternal diameter packed with Waters Symmetry C8 stationary phase having3.5 μm particle size. The mobile phase flow rate was 1.0 mL/minute,temperature was controlled at 25° C., and impurity concentration wasdetermined by comparison of absorbance at 254 nm, measured using avariable wavelength uv detector, with that of an external Compound (I)reference standard.

Dissolution

Dissolution was determined according to the general procedure of theUnited States Pharmacopoeia (USP) using Apparatus 2 with 900 mL of 0.1MPhosphate buffer at pH 7.8 as dissolution medium and a stirrer speed of50 rpm. At 15, 30 and 45 minutes, 10 ml of dissolution media waswithdrawn and filtered through a 0.45 μm PTFE filter, discarding thefirst 2 ml of filtrate. The amount of Compound (I) in solution wasmeasured using an HPLC procedure similar to that described above, exceptthat the method was operated under isocratic conditions using as mobilephase water:acetonitrile orthophosphoric acid in the ratio 700:300:2.The sample volume was 50 μL, the stationary phase was JonesChromatography Genesis C18, the mobile phase flow rate was 1.5mL/minute, temperature was controlled at 40° C., and the measurementwavelength was 224 nm.

Friability

Twenty tablets were accurately weighed and placed in a rotating drum(Copley TA-10 or equivalent). The drum was rotated 100 times and thetablets removed. Loose dust was removed from the tablets and the tabletsre-weighed. The friability is expressed as the loss of mass and it iscalculated as a percentage of the initial mass.

EXPERIMENTAL AND RESULTS

In the following results and tables where “ND” is stated, it is to beunderstood that this refers to a value lower than the detection limitsof the methods used.

Example 1 Compound (I) Forced Degradation Study

The stability of Compound (I) drug substance at an initial concentrationof 0.5 mg/mL in solution in aqueous buffers, in the dark at room andelevated temperature over a period of 24 hours, as shown in Table 2, andexposed to light at room temperature (RT) over a period of 2 hours, asshown in Table 3, was investigated in a forced degradation study. Theresults are summarised in Tables 2 and 3. “ND” in Tables 2 and 3 refersto “not determined”

TABLE 2 Compound (I) forced degradation study (0.5 mg/mL solutions)(solutions protected from light) pH 1.2 pH 3.0 pH 7.2 pH 11.0 RT 37° C.RT 37° C. RT 37° C. RT 37° C. Compound (I), % w/w 97.57/ 96.69/ 99.45/99.43/ 99.14/ 98.73/ 98.68/ 99.17/ (initial/24 hours) 23.04 0.89 84.7096.56 99.45 99.17 94.21 94.50 Compound (I) 1.99/ 1.58/ ND/ ND/ ND/ ND/0.07/ ND/ formyl hydrazide, % w/w 59.83 32.16 1.66 3.09 ND ND 1.35 4.16(initial/24 hours) Compound (I) hydrazide, ND/ ND/ ND/ ND/ ND/ ND/ ND/ND/ % w/w (initial/24 hours) 13.87 47.34 <0.05 ND <0.05 <0.05 ND <0.05

TABLE 3 Compound (I) forced degradation study (solutions exposed tolight at room temperature) pH 1.2 pH 3.0 pH 7.2 pH 11.0 Compound (I),98.82/82.33 99.39/95.76 98.78/97.04 99.91/98.66 % w/w (initial/ 24hours) Compound (I)  1.39/16.35 0.05/0.30 ND/ND <0.05/0.15   formylhydrazide, % w/w (initial/ 24 hours) Compound (I)  ND/0.32 ND/ND ND/NDND/ND hydrazide, % w/w (initial/ 24 hours)

Example 2 Stability Study for Lactose-Based Tablets

Compound (I) lactose-based tablets were manufactured using wetgranulation, compression and film coating processes, using theformulations shown in Table 4. The powdered ingredients (other than thebinder and lubricant) were charged to a suitable mixer and mixed toproduce a uniform distribution of drug substance (Compound (I)). Anaqueous binder solution (povidone) was prepared and added to the powderswith further mixing until a suitable wet mass was formed. The wet masswas passed through a screen (mesh size 9 mm) and the resultant granulesdried to an appropriate moisture content (less than 2% by weight). Thelubricant was added to the dry granules, which were then passed througha suitable screen (mesh size 1.4 mm) prior to blending. The blendedgranules were compressed into tablet cores using tableting equipment(using a rotary press to give tablets of the required hardness,disintegration and appearance). The compressed cores were then coatedwith an aqueous suspension of film coating components using a perforateddrum coater (for example an O'hara coater).

TABLE 4 Active tablet (10 mg, lactose monohydrate filler) Ingredientmg/tablet Function Tablet core % of core weight Compound (I) 10.0 4.00Drug substance Lactose monohydrate 222.5 89.00 Filler Croscarmellosesodium 10.0 4.00 Disintegrant Povidone K29/32 5.0 2.00 Binder Magnesiumstearate 2.5 1.00 Lubricant Core tablet weight 250.0 Tablet coating % ofcoating weight Hypromellose 606 3.75 65.22 Film-former Polyethyleneglycol 300 0.75 13.04 Plasticiser Titanium dioxide 1.25 21.74 Opacifier% of core weight Nominal coating weight 5.75 2.30

These tablets were tested for Compound (I) assay and impuritiesimmediately after preparation and after periods of storage under variousconditions of temperature and relative humidity (RH), as shown in Table5.

TABLE 5 Stability data summary—lactose tablets 25° C./ 40° C./ 60% RH75% RH 50° C. Light (36 (12 (6 (10 Initial months) months) months) days)10 mg Compound (I) 9.8 9.9 9.8 9.9 9.9 tablets (mg/tablet) (Table 4)Compound (I) <0.05 0.13 0.19 0.09 <0.05 formyl hydrazide (%) Total <0.050.13 0.19 0.09 0.38 impurities (%)

Example 3 Excipient Compatibility Study

Possible materials were evaluated in accordance with the experimentaldesign matrix shown in Table 6.

TABLE 6 Experimental Design Matrix Exp Filler (A) Disintegrant (B)Binder (C) 1 Magnesium carbonate, heavy Crospovidone HPMC 2 Magnesiumcarbonate, heavy Croscarmellose sodium Povidone 3 Calcium phosphatedihydrate Crospovidone HPMC 4 Calcium phosphate dihydrate Croscarmellosesodium Povidone 5 Microcrystalline cellulose Croscarmellose sodium HPMC6 Microcrystalline cellulose Crospovidone Povidone 7 Mannitol (directcompression) Croscarmellose sodium HPMC 8 Mannitol (direct compression)Crospovidone Povidone

For each experiment, the following formulation was used:

TABLE 7 Tablet composition used in the excipient compatibility studyIngredient mg/tablet % w/w Function Compound (I) 10.00 6.67 Drugsubstance (See Table 6) 129.50 86.33 Filler (See Table 6) 6.00 4.00Disintegrant (See Table 6) 3.00 2.00 Binder Magnesium stearate 1.50 1.00Lubricant Core tablet weight 150.00

Tablet cores for this study were manufactured using wet granulation,compression processes using an analogous wet granulation method to thatdescribed in Example 2. These tablet cores were tested for Compound (I)assay/impurities and dissolution, immediately after preparation andafter periods of storage under various conditions of temperature andrelative humidity (RH), as shown in Table 8.

TABLE 8 Summary of results from the excipient compatibility study 70° C.70° C./80% RH Ex Initial 7 days 14 days 7 days 14 days Light 1Dissolution (%) 100.99 98.10 94.01 91.80 90.00 98.10 Total Impurities(%) 0.215 2.877 3.798 3.580 5.030 3.174 2 Dissolution (%) 89.58 94.5783.00 22.82 20.36 94.57 Total Impurities (%) 0.227 2.639 3.522 2.0283.362 2.996 3 Dissolution (%) 54.64 54.43 52.70 70.45 50.81 54.43 TotalImpurities (%) 0.107 0.499 0.761 0.261 0.328 2.172 4 Dissolution (%)66.38 58.41 65.45 51.88 46.54 58.41 Total Impurities (%) 0.096 0.4260.543 0.165 0.320 2.693 5 Dissolution (%) 96.54 94.79 98.30 94.86 96.4794.79 Total Impurities (%) 0.078 0.187 0.238 0.115 0.139 1.731 6Dissolution (%) 98.79 96.21 98.77 96.29 98.05 96.21 Total Impurities (%)0.077 0.097 0.134 0.163 0.206 1.904 7 Dissolution (%) 94.97 94.61 94.8169.23 68.48 94.61 Total Impurities (%) 0.141 0.113 0.143 0.121 0.1201.145 8 Dissolution (%) 96.79 101.79 100.06 98.66 99.58 101.79 TotalImpurities (%) 0.078 0.078 0.099 0.168 0.201 1.246 NB: Table quotesdissolution (% release) measured at 45 mins.

Example 4 Mannitol/Microcrystalline Cellulose Formulations

Placebo tablet cores containing (i) mannitol and (ii) mannitol andmicrocrystalline cellulose were investigated for their tensile strengthand disintegration time.

Example 41 Placebo Tablet Cores Manufactured Using Mannitol as Filler

TABLE 9 Placebo tablet formulation (mannitol filler) Ingredientmg/tablet % w/w Function Mannitol 266.63 91.0 Filler Croscarmellosesodium 11.72 4.0 Disintegrant Povidone K29/32 11.72 4.0 Binder Magnesiumstearate 2.93 1.0 Lubricant Core tablet weight 293

The formulation described in Example 41 was prepared by a wetgranulation and compression process, using an analogous method to thatdescribed in Example 2 except that the binder was added as a powder atthe dry mix stage, and water was used as the granulating medium at thewet mix stage.

Example 4ii Placebo Tablet Cores Manufactured Using Mannitol andMicrocrystalline Cellulose as Filler

TABLE 10 Placebo tablet (mannitol/microcrystalline cellulose filler)Ingredient mg/tablet % w/w Function Mannitol 120.12 45.5 FillerMicrocrystalline cellulose 120.12 45.5 Filler Croscarmellose sodium10.56 4.0 Disintegrant Povidone K29/32 10.56 4.0 Binder Magnesiumstearate 2.64 1.0 Lubricant Core tablet weight 264.00

The formulation described in Example 4ii was prepared by wet granulationand compression processes analogous to those described in Example 2,except that the binder was added as a powder at the dry mix stage, andwater was used as the granulating medium at the wet mix stage.

Tablet cores from Examples 4i and 4ii were tested for hardness anddisintegration time immediately after manufacture and after 4 weeksstorage under various conditions of temperature and RH, as shown inTable 11.

TABLE 11 Stability data summary for Placebo Tablets from Examples i(tablet described in Table 9) and Example ii (tablet described in Table10) Hardness (kp) Disintegration Time (min.) 25° C./ 40° C./ 25° C./ 40°C./ Initial 60% RH 75% RH Initial 60% RH 75% RH Example 4i 7.056 8.48417.16 1.76 2.18 6.25 (mean of 10 tablets) Example 4ii 8.005 7.750 6.9540.63 0.68 0.79 (mean of 10 tablets)

Example 5 Formulation

A 10 mg tablet formulation is shown in Table 12.

TABLE 12 Active tablet (10 mg, mannitol/microcrystalline cellulosefiller) Ingredient mg/tablet Function Tablet core % of core weightCompound (I) 10.000 6.67 Drug substance Mannitol 110.750 73.83 FillerMicrocrystalline cellulose 18.750 12.50 Filler Croscarmellose sodium4.500 3.00 Disintegrant Povidone K29/32 4.500 3.00 Binder Magnesiumstearate 1.500 1.00 Lubricant Core tablet weight 150.000 Tablet coating% of coating weight Hypromellose 2910 3.281 62.50 Film former Titaniumdioxide 1.563 29.77 Opacifier Polyethylene glycol 400 0.328 6.25Plasticiser Iron oxide yellow 0.059 1.12 Colouring agent Iron oxide red0.014 0.27 Colouring agent Iron oxide black 0.004 0.08 Colouring agent %of core weight Nominal coating weight 5.250 3.50

The tablets may be prepared using, for example, the following wetgranulation process:

Compound (I) (1.334 kg), mannitol (Partek™ M200, Merck, 14.76 kg),microcrystalline cellulose (Avicel™ PH101, FMC, 2.5 kg), croscarmellosesodium (Ac-Di-Sol™, FMC, 600 g) and poyvinylpyrrolidinone (Plasdone™K29/32, ISP, 600 g) are mixed together in a Vector GMX75 high shearblender. Water (4.5 kg, addition rate of 1.2 kg/minute) is sprayed intothe mixture and the mixture granulated for about 5 minutes. The granulesare dried in an O'Hara 30/60 fluid bed dryer (inlet air temperature 70°C., air flow rate sufficient to fluidise the granule bed) to a moisturecontent of <2% w/w and the dried granules milled using a Quadro Co mil194 (screen mesh 0.062 inches (1.6 mm), 400 rpm).

Four of the above portions are combined and 800 g magnesium stearateadded. The 80 kg batch is transferred to a Pharmatech BV400 blender andthe mixture blended. The mixture is then compressed into tablets (150 mgcompression weight, plain, round, bi-convex 7 mm diameter) using an IMAKilian Synthesis 500 tablet press (80,000 tablets per hour, 7.5 kNcompression force). The tablets are then coated using a Manesty Premier200 coater with Opadry Beige (Colorcon 03B27164, 315 g/kg aqueoussolution). The total coating solution applied is equivalent to 35 g/kgof Opadry per mass of tablet cores.

The tablets may also be prepared using aqueous PVP as the granulationliquid instead of water in the process described above.

A 15 mg tablet formulation is shown in Table 12A.

TABLE 12A Ingredient mg/tablet Function Tablet core % of core weightCompound (I) 15.000 6.67 Drug substance Mannitol 166.125 73.83 FillerMicrocrystalline cellulose 28.125 12.50 Filler Croscarmellose sodium6.750 3.00 Disintegrant Povidone K29/32 6.750 3.00 Binder Magnesiumstearate 2.250 1.00 Lubricant Core tablet weight 225.000 Tablet coating% of coating weight Hypromellose 2910 4.922 62.50 Film former Titaniumdioxide 2.345 29.77 Opacifier Polyethylene glycol 400 0.492 6.25Plasticiser Iron oxide yellow 0.089 1.12 Colouring agent Iron oxide red0.022 0.27 Colouring agent Iron oxide black 0.006 0.08 Colouring agent %of core weight Nominal coating weight 7.876 3.50

The 15 mg tablets may be prepared using an analogous method to thatdescribed for the preparation of the 10 mg tablets shown in Table 12.

A stability study was carried out on batches of beige film-coated 10 mgtablets prepared as described in Table 12; and the results aresummarised in Table 13.

TABLE 13 Stability data summary for mannitol/ microcrystalline celluloseformulations 25° C./ 40° C./ 60% RH 75% RH 50° C. Light (12 (12 (6 (10Initial months) months) months) days) 10 mg Compound (I) 9.5 9.6 9.8 9.59.8 tablets (mg/tablet) (Table Compound (I) <0.05 ND 0.10 <0.05 <0.0512) formyl hydrazide (%) Total impurities <0.05 ND 0.10 <0.05 <0.05 (%)Dissolution (% 101 94 93 97 101 release after 45 minutes) Hardness (mean15.53 14.13 16.37 N/A N/A of 15 tablets, kp) Disintegration 7.58 6.858.85 N/A N/A time (min.)

Example 6 Comparison of Mannitol Grades

Mannitol is available in two grades for use as a pharmaceuticalexcipient in tablet manufacture: a wet granulation grade, for examplePearlitol® C supplied by Roquette Freres S.A., and a direct compressiongrade, such as Parteck M™ supplied by Merck Chemicals Ltd.

Three batches of tablet cores, as described in Table 12, were processedusing the mannitol grade and manufacturing process as indicated in Table14.

TABLE 14 Batches manufactured in the comparison of mannitol gradesMannitol Grade Manufacturing Process Batch 1 Wet Granulation WetGranulation Batch 2 Direct Compression Wet Granulation Batch 3 DirectCompression Direct Compression

The direct compression tablets were manufactured using a directcompression process. The Compound (I) and the mannitol were sieved intoa bowl and then mixed together in a planetary mixer for 10 minutes. Theremaining mannitol, the microcrystalline cellulose, the croscarmellosesodium and the Povidone K29/32 were then added to the bowl and themixture was mixed for a further 10 minutes. The magnesium stearate wasthen added through a sieve and the mixture was mixed for a further 5minutes. The resultant mixture was then compressed into tablet cores,using a target compression force of 5.0 KN.

The tablets prepared using wet granulation were prepared using ananalogous method to that described in Example 2.

The physical characteristics of the three batches of tablet cores weredetermined and dissolution was measured using the procedure describedpreviously, except that the dissolution medium was 500 mL pH1.4 sodiumchloride/hydrochloric acid buffer (0.1M) and the stirrer speed was 75rpm. The results are summarised in Table 15.

TABLE 15 Physical characteristics of the batches in the comparison ofmannitol grades Dissolution Hardness Thickness (% release afterFriability (kp) (mm) 45 minutes) (%) Batch 1 2.96 3.77 N/A 0.30 Batch 25.40 3.95 89.7 0.03 Batch 3 8.89 3.92 87.3 0.03

Example 7 Mannitol/Microcrystalline Cellulose Formulations ContainingCompound (I)

Two experimental batches were manufactured comprising Compound (I) andmagnesium stearate in the same proportions as in the final formulation(Table 12), with an increased binder and disintegrant content (from 3%to 5%), without microcrystalline cellulose (Table 16) and withmicrocrystalline cellulose content increased from 12.5% to 25% (Table17). The resulting tablet cores were tested for hardness immediatelyafter manufacture and after storage for 16 months at 25° C./65% RH(Table 18).

TABLE 16 Formulation of Compound (I) with Mannitol filler Ingredientmg/tablet % w/w Function Tablet core Compound (I) 10.000 6.67 Drugsubstance Mannitol 123.5 82.33 Filler Croscarmellose sodium 7.500 5.00Disintegrant Povidone K29/32 7.500 5.00 Binder Magnesium stearate 1.5001.00 Lubricant Core tablet weight 150.000

TABLE 17 Formulation of Compound (I) with mixedmannitol/microcrystalline cellulose filler Ingredient mg/tablet % w/wFunction Tablet core Compound (I) 10.000 6.67 Drug substance Mannitol86.000 57.33 Filler Microcrystalline cellulose 37.500 25.00 FillerCroscarmellose sodium 7.500 5.00 Disintegrant Povidone K29/32 7.500 5.00Binder Magnesium stearate 1.500 1.00 Lubricant Core tablet weight150.000

TABLE 18 Hardness Data (KP) Time of 65 weeks storage Manufacture (roomtemperature) Mannitol formulation (Table 16) 11.6 7.43Mannitol/microcrystalline cellulose 9.8 7.52 formulation (Table 17)

1-19. (canceled)
 20. A pharmaceutical composition comprising zibotentan,a pigmented film-coat and a filler.
 21. A pharmaceutical composition asclaimed in claim 20 wherein, the filler is microcrystalline celluloseand/or mannitol.
 22. A pharmaceutical composition as claimed in claim 20in the form of a tablet or a capsule.
 23. A pharmaceutical compositioncomprising a filler, zibotentan and a coating comprising one or morecoloring agents wherein the pharmaceutical composition is in the form ofa tablet.
 24. A pharmaceutical composition as claimed in claim 23 with acoating comprising three coloring agents.
 25. A pharmaceuticalcomposition as claimed in claim 23 wherein, the coating contains from0.5 to 10% by weight of coloring agent.
 26. A pharmaceutical compositionas claimed in claim 25 wherein, it contains 1 to 2% by weight ofcoloring agent.
 27. A pharmaceutical composition as claimed in eitherclaim 23 wherein, the coating comprises an iron oxide pigment.
 28. Apharmaceutical composition as claimed in claim 27 wherein, the coatingcomprising iron oxide yellow, iron oxide red and iron oxide black.
 29. Apharmaceutical composition comprising a filler, zibotentan and a coatingcomprising one or more opacifiers wherein the pharmaceutical compositionis in the form of a tablet.
 30. A pharmaceutical composition as claimedin claim 29 wherein, the coating comprising titanium dioxide.
 31. Apharmaceutical composition as claimed in claim 29 wherein, the coatingcontains from 20 to 40% by weight of opacifier.
 32. A pharmaceuticalcomposition as claimed in claim 31 wherein, the coating contains 27.5 to31.5% by weight of opacifier.
 33. A pharmaceutical composition asclaimed in claim 29 wherein, the coating comprises one or more filmformers.
 34. A pharmaceutical composition as claimed in claim 29wherein, the coating is between 1 to 10% by weight of the tablet coreweight.
 35. A pharmaceutical composition as claimed in claim 34 wherein,the coating is between 3 to 6% by weight of the tablet core weight. 36.A composition as claimed in claim 35 wherein, the coating is 3 to 4% byweight of the tablet core weight.
 37. A pharmaceutical composition asclaimed in claim 20 wherein, the coating comprises one or more filmformers.
 38. A pharmaceutical composition as claimed in claim 20wherein, the coating is between 1 to 10% by weight of the tablet coreweight.
 39. A pharmaceutical composition as claimed in claim 23 wherein,the coating comprises one or more film formers.